Regulatory gene-chemokine networks in the formation of hemodialysis AVF stenosis

PROJECT SUMMARY/ABSTRACT: More than 435,000 patients in the US have end stage renal disease (ESRD), a population expected to double in the next decade. The long-term goal of this current proposal and research program is to improve the care of patients with ESRD, the vast majority of who use long-term hemodialysis as their mode of renal replacement therapy. These patients require highly functioning vascular access for optimal therapeutic adequacy. Hemodialysis vascular access failure is frequently from venous stenosis secondary to neointimal hyperplasia (VNH). Our preliminary data demonstrate an important role for the Iex-1/Mcp-1 pathway in VNH. We show that: 1. IEX-1 staining is increased in venous stenoses removed from patients with AVF. 2. Venous stenoses in AVF removed from a Iex-1 knockout (KO) mice with chronic kidney disease (CKD) have a significant increase in lumen vessel area, decrease in neointima area with a significant increase in apoptosis, decrease in cellular proliferation, significant reduction in ?-SMA and Ly6C monocyte staining, and a significant decline in MCP-1 and MMP-9 immunostaining. 3. Gene expression of Mcp-1, Fgf-1, and Tgf-? are all significantly decreased in venous segments removed from Iex-1 KO mice implying that Iex-1 decreases fibrotic and inflammatory function. 4. Adventitial delivery of nanoparticles composed of polylactic-co-glycolic acid (PLGA) with calcitriol significantly reduces Iex-1 gene expression at day 7 and VNH 28 days later (P